JP7384365B2 - 口腔乾燥症を診断するための唾液バイオマーカー及びその用途 - Google Patents
口腔乾燥症を診断するための唾液バイオマーカー及びその用途 Download PDFInfo
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Description
前記遺伝子は、前記蛋白質を暗号化する核酸を言う。前記遺伝子の発現レベルは、前記蛋白質を暗号化するmRNAの発現レベルでもある。該mRNAの発現レベルは、mRNAの相対的量、または絶対的な量でもある。前記遺伝子の発現レベルの測定は、mRNAの量を測定することでもある。
〔1.口腔乾燥症患者の唾液試料の準備〕
漢陽大学校から、正常対照群(n=3)と、口腔乾燥症と診断された患者とからの唾液試料を収集した。該口腔乾燥症は、唾液腺分泌と口腔粘膜状態とに対する臨床検査、及び唾液腺スキャンにより、唾液腺機能に対する評価によって診断した。該唾液腺機能は、唾液腺組織検査を施し、唾液腺組織の状態と、唾液腺実質周辺におけるリンパ球の浸透いかんとにより、スコア1ないしスコア5に分類した。スコア1、スコア2、及びスコア3ないし5の3群に分類し、唾液サンプリングを行った。
4個グループの総12個の唾液試料を、3k遠心分離フィルタ(Amicon Ultra,Millipore)を使用して濃縮した。3k遠心分離フィルタに、400μlの水(HPLC等級、J.T Baker)を2回加え、400μlの0.1%(w/v)SDSが含まれた10mMTris緩衝液(pH8.0)を2回加えてフィルタを準備した。
プロテオーム分析のために、2.で得られた4個のグループの12個の個別試料55μgを、NuPAGEゲル(4%ないし12%のBis-Trisゲル、Invitrogen,Carlsbad,CA、米国)を使用し、分子量によって分離した。該ゲルを、クマシーブリリアントブルー(Coomassie Brillant Blue R-250)で染色した(図1)。12個の個別試料に対して染色されたゲルを、12個の切片(slice)で分け、それぞれのゲル切片をマイクロ遠心分離チューブに移した。それぞれのゲル切片に含まれた蛋白質に対し、56℃で二硫化結合を還元させた後、25℃の暗い環境でアルキル化させ、トリプシンで一晩分解させた。次に、67%(v/v)のアセトニトリル(ACN:acetonitrile)/5%(v/v)のギ酸(FA:formic acid)(Wako Pure Chemicals、大阪、日本)溶液でペプチドを抽出した。抽出されたペプチドは、Speedvacで乾燥させた後、20μlの0.4%(v/v)酢酸に溶解させた。
0.4%酢酸に再懸濁した 3.で得たそれぞれの試料10μlを、Eksigent MDLCシステム(Eksigent Technologies, Dublin,CA、米国)上において、逆相Magic C18AQカラム(15cmX75μm)に注入した。前記カラムを、95%の緩衝液A(0.1%(v/v)のギ酸を含む100%(v/v)の水)と5%の緩衝液B(0.1%(v/v)のギ酸を含む100%(v/v)のACN)とを混合した緩衝液で平衡化させた。作業流速は、次の勾配条件において、0.35μl/分(min)にした:
0分ないし5分において、0-8%緩衝液B;5分ないし85分において、8-30%緩衝液B;85分ないし90分において、30-70%緩衝液B;90分ないし95分において、70%緩衝液B;95分ないし100分において、70-2%緩衝液B;並びに100分ないし110分において、2%緩衝液B
ナノHPLCシステムを、LTQ XL-Orbitrap質量スペクトロメーター(Thermo Scientific,San Jose,CA、米国)に装着させた。噴霧電圧(spray voltage)は、2.5kVに設定し、加熱された毛細管の温度は、250℃に設定した。調査全体スキャンMSスペクトラ(Survey full-scan MS spectra)(300ないし1,800m/z)を、1マイクロスキャン(microscan)及び60,000の解像度(resolution)で得て、先導物質(precursor)を選別し、電荷状態測定のためのプレビューモードを設定した。プレビューの調査スキャンから、10個の最も強力なイオンに係わるMS/MSスペクトラを、下記のようなオプションで、全体スキャンに係わるイオントラップから得た:分離間隔(isolation width) 2m/z(質量対電荷);標準化された衝突エネルギー(collision energy) 35%;動的排除時間(dynamic exclusion duration) 360秒(sec)。+1電荷、及び電荷状態が定まっていない先導物質は、データ従属的に(data-dependent)得られる間に廃棄した。
正常対照群と口腔乾燥症患者群との3個のグループから、唾液試料をそれぞれ3個ずつ収集した総12個のサンプルに存在する蛋白質の相対的な存在量を、ラベルフリー定量強度分析法(LFQ強度(label-free quantification intensity)に基づいて算出した。MaxQunat1.5.8.3を使用してLFQ強度を抽出した。次に、それぞれの蛋白質に係わるLFQ強度を、Perseusを利用し、相対的な定量分析を行った。蛋白質が存在しないか、あるいは検出限界以下である場合にも、零点(null)数値を補償した。正常対照群と、口腔乾燥症による患者群とのグループ間の倍数差を計算するために、正規分布(normal distribution)において、広さ0.3から1.8ほどをダウンシフトし、欠測値(missingvalue)を充填した。統計的な有意性は、正常対照群と、口腔乾燥症による患者群との3個の個別試料でもって、ANOVA検定から得たLFQ強度について行い、p値が0.05未満である場合、統計的に有意であると見なした。
LFQ強度分析から、正常対照群と、口腔乾燥症によるグループとの12個の個別試料において、総703種の蛋白質を同定した。同定された蛋白質のうち、p値が0.05未満である蛋白質51種を確認した。同定された蛋白質と、p値が0.05未満と、統計的に有意な蛋白質とを分析し、個数をベン図式で示した結果を図2に示した。
Claims (13)
- NUCB2(Nucleobindin-2)遺伝子の発現レベル、あるいは蛋白質またはその断片の発現レベルを測定する製剤を含む、口腔乾燥症診断用組成物。
- 唾液試料において検出するためのものである、請求項1に記載の組成物。
- 前述のNUCB2遺伝子の発現レベルは、正常対照群の発現レベルに比べて低下する、請求項1に記載の組成物。
- 前記製剤は、
前記蛋白質またはその断片に特異的に結合する抗体、その抗原結合断片またはアプタマー、または
前記蛋白質またはその断片を暗号化するポリヌクレオチドと同一であるか、またはそれに相補的なポリヌクレオチドを含む核酸である、請求項1に記載の組成物。 - 前記抗体は、ポリクローナル抗体またはモノクローナル抗体である、請求項4に記載の組成物。
- 前記核酸は、プライマー、プローブまたはアンチセンスオリゴヌクレオチドである、請求項4に記載の組成物。
- KV108(immunoglobulin kappa variable 1-8)、GSLG1(golgi apparatus protein 1)、FAM3B(protein FAM3B)、MUC21(mucin-21)、RB11A(Ras-related protein Rab-11A)、LYSC(Lysozyme C)、CALL3(calmodulin-like protein 3)、A1BG(alpha-1B-glycoprotein)、A1AG1(alpha-1-acid glycoprotein 1)、CALR(calreticulin)、PLMN(plasminogen)、ECM1(extracellular matrix protein 1)、ANXA6(Annexin A6)、WDR1(WD repeat-containing protein 1)、ILEU(leukocyte elastase inhibitor)、FETUA(alpha-2-HS-glycoprotein)、MNDA(myeloid cell nuclear differentiation antigen)、MMP9(matrix metalloproteinase-9)、NGAL(neutrophil gelatinase-associated lipocalin)、DOPD(D-dopachrome decarboxylase)、MMP8(neutrophil collagenase)、A1AT(alpha-1-antitrypsin)、IGG1(Immunoglobulin gamma-1 heavy chain)、PDCD6IP(Programmed cell death 6-interacting protein)、PTGR1(Prostaglandin reductase 1)、FAM3D、ZG16B(Zymogen granule protein 16 homolog B)、ANT3(Antithrombin-III)、ATPA(ATP synthase subunit alpha, mitochondrial)、HRG(histidine-rich glycoprotein)、H15(histone H1.5)、H2B1L(histone H2B type 1-L)、PCBP1(poly(rC)-binding protein 1)及びPTPRJ(receptor-type tyrosine-protein phosphatase eta)からなる群のうちから選択された遺伝子の発現レベル、あるいは蛋白質またはその断片の発現レベルを測定する製剤をさらに含む、請求項1に記載の組成物。
- NUCB2遺伝子の発現レベル、あるいは蛋白質またはその断片の発現レベルを測定する製剤を含む、口腔乾燥症診断用キット。
- KV108、GSLG1、FAM3B、MUC21、RB11A、LYSC、CALL3、A1BG、A1AG1、CALR、PLMN、ECM1、ANXA6、WDR1、ILEU、FETUA、MNDA、MMP9、NGAL、DOPD、MMP8、A1AT、IGG1、PDCD6IP、PTGR1、FAM3D、ZG16B、ANT3、ATPA、HRG、H15、H2B1L、PCBP1及びPTPRJからなる群のうちから選択された遺伝子の発現レベル、あるいは蛋白質またはその断片の発現レベルを測定する製剤をさらに含む、請求項8に記載のキット。
- 口腔乾燥症が疑われる個体から分離された唾液試料において、NUCB2遺伝子の発現レベル、あるいは蛋白質またはその断片の発現レベルを測定する段階と、
前記測定された発現レベルを、正常対照群の発現レベルと比較する段階と、を含む、口腔乾燥症の診断に必要な情報を提供するためにバイオマーカーを検出する方法。 - 前記測定する段階は、前記唾液試料と、前記蛋白質またはその断片に特異的に結合する抗体、その抗原結合断片またはアプタマーと、をインキュベーションさせるか、あるいは前記遺伝子をコーディングするポリヌクレオチドと同一であるか、あるいはそれに相補的なポリヌクレオチドをインキュベーションさせる段階を含む、請求項10に記載の方法。
- 前記測定する段階は、LC-MSによって遂行される、請求項10に記載の方法。
- KV108、GSLG1、FAM3B、MUC21、RB11A、LYSC、CALL3、A1BG、A1AG1、CALR、PLMN、ECM1、ANXA6、WDR1、ILEU、FETUA、MNDA、MMP9、NGAL、DOPD、MMP8、A1AT、IGG1、PDCD6IP、PTGR1、FAM3D、ZG16B、ANT3、ATPA、HRG、H15、H2B1L、PCBP1及びPTPRJからなる群のうちから選択された遺伝子の発現レベル、あるいは蛋白質またはその断片の発現レベルを測定する段階をさらに含む、請求項10に記載の方法。
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